The studies in this application are designed to equip the principal investigator, Dr. Daniel Vatner, with the technical and scientific expertise necessar to achieve independence as a physician-scientist, performing translational research, both patient-oriented research and basic science research, studying the pathophysiology and treatment of insulin resistance and diabetes. The work described in this application will be carried out by Dr. Vatner under the supervision of Drs. Varman Samuel and Gerald Shulman in the Department of Internal Medicine, Section of Endocrinology, at the Yale University School of Medicine. Through this award, Dr. Vatner will broaden his scientific and technical knowledge bases, and will generate data for publications and future independent award applications, facilitating further career advancement. During the period of this award, Dr. Vatner will be performing the research described in this application, frequently meeting with his advisors, completing coursework, and attending scientific meetings. Our long-term objective is to better understand the underlying physiology that predisposes some obese individuals to insulin resistance and protects other individuals from insulin resistance, laying the groundwork for novel therapies for the prevention and treatment of insulin resistance and type 2 diabetes. Specifically, Dr. Vatner will: 1. evaluate the role of substrate-regulated lipogenesis in the development of diabetic dyslipidemia and hepatic steatosis in rodents and humans; and 2. assess differences in adipose tissue function between obese subjects with and without insulin resistance, looking at differences in postprandial fat storage by adipose and liver. As lipid deposition in insulin-responsive organs such as liver is central to the development of insulin resistance, these studies have the potential to identify changes in adipose biology that protect vs. predispose an individual to type 2 diabetes. We will use stable isotope tracers in rats and humans to measure rates of hepatic fatty acid esterification. We will use PET-CT in mice and humans to assess for differences in postprandial lipid uptake in adipose and liver.